Determinants of protein–ligand complex formation in the thyroid hormone receptor α: A molecular dynamics simulation study

The thyroid hormone receptors (TR) are members of the nuclear receptor superfamily that regulate growth, development, and metabolic processes in a ligand-dependent manner. Because of their involvement in many aspects of human health, TRs are emerging as important therapeutic targets with thyroid hormone analogues having potential applications in atherosclerosis and obesity. Understanding the molecular mechanisms of binding between the TR and its ligands is thus of fundamental importance for its implications for regulation of gene activity and for its applications in the pharmacological industry. In this work we have carried out atomistic molecular dynamics (MD) simulations of three protein–ligand complexes formed between the ligand binding domain (LBD) of the TRα and three different ligands: the thyroid hormone T3, the natural thyroid hormone analogue Triac, and the synthetic ligand GC1. The conformational fluctuations of the protein and ligands, the microscopic properties of the surrounding water molecules, and direct and water-mediated ligand–protein interactions have been studied in detail. Our results reveal that the formation of the protein–ligand complex is associated with the loss of flexibility of the individual molecules and the presence of highly structured dynamically restricted water molecules in the ligand-binding cavity of these complexes.